Project Summary/Abstract Consensus guidelines for U.S. cervical cancer screening since 2012 have recommended that women can exit screening at age 65 years assuming no history of abnormal results in the past 10-20 years. Although recent modeling studies have corrected for hysterectomy and found evidence that extending screening to ages 70 or 75 years may warrant consideration, areas of uncertainty regarding the optimal screening end criteria remain. These include the potential impact of declining rates of hysterectomy and changes in life expectancy, which may impact the absolute number of women who are at risk for cervical cancer and can benefit from screening at older ages. There is also uncertainty about whether women who came of age during the sexual revolution (and are now entering the age range to end screening) have a greater baseline risk for cancer that may remain even after a lifetime of screening. There is also uncertainty at the woman-level regarding the clinical implications of a newly-detected HPV infection in older women. On one hand, the HPV infection may be newly acquired, conferring similar risk of cervical disease as incident infections in younger women. On the other hand, the HPV infection may be a ?reactivation? of a previously-acquired latent infection and may therefore confer differential risk for cervical disease than a truly new infection. The extent to which these scenarios impact the optimal screening end age for a particular woman has not been studied, but can be explored through modeling. We propose to conduct a comparative modeling study reexamining assumptions about the natural history of HPV infection in older women in order to assess existing and new strategies for termination of screening in U.S. women. Specifically we propose to: Aim 1. To examine the relative impacts of HPV reactivation versus new infection on cervical cancer risk at the individual woman level; Aim 2. To compare the harms and benefits of current and alternative criteria (ages, algorithms, and tests) for ending screening under these alternative scenarios, for HPV-positive women with either new or reactivated infections; Aim 3. To identify areas of uncertainty that could benefit from a value of information analysis. This analysis will allow greater understanding of the impact of natural history assumptions on cancer incidence in subgroups of older women, depending on the details of their exposure to HPV. Additionally, we will evaluate the impact of natural history and screening termination criteria on a variety of harm and benefit metrics for cervical cancer screening.